Plasma 24S-hydroxycholesterol levels in elderly subjects with late onset Alzheimer's disease or vascular dementia: a case-control study

<p>Abstract</p> <p>Background</p> <p>In central nervous system cholesterol cannot be degraded but is secreted into circulation predominantly in the form of its polar metabolite 24(<it>S</it>)-hydroxycholesterol (24S-OH-Chol). Some studies suggested an association between 24S-OH-Chol metabolism and different neurological diseases including dementia. A possible decrease in 24S-OH-Chol plasma levels has been reported late onset Alzheimer's disease (LOAD) and vascular dementia (VD), but results of previous studies are partially contradictory.</p> <p>Methods</p> <p>By high-speed liquid chromatography/tandem mass spectrometry we evaluated the plasma levels of 24S-OH-Chol in a sample of 160 older individuals: 60 patients with LOAD, 35 patients with VD, 25 subjects affected by cognitive impairment no-dementia (CIND), and 40 (144 for genetics study) cognitively normal Controls. We also investigated the possible association between PPARgamma Pro12Ala polymorphism and dementia or 24S-OH-Chol levels.</p> <p>Results</p> <p>Compared with Controls, plasma 24S-OH-Chol levels were higher in LOAD and lower in VD; a slight not-significant increase in CIND was observed (ANOVA p: 0.001). A positive correlation between 24S-OH-Chol/TC ratio and plasma C reactive protein (CRP) levels was found in the whole sample, independent of possible confounders (multiple regression p: 0.04; r²: 0.10). This correlation was strong in LOAD (r: 0.39), still present in CIND (r: 0.20), but was absent in VD patients (r: 0.08). The PPARgamma Pro12Ala polymorphism was not associated with the diagnosis of LOAD, VD, or CIND; no correlation emerged between the Ala allele and 24S-OH-Chol plasma levels.</p> <p>Conclusions</p> <p>Our results suggest that plasma 24S-OH-Chol levels might be increased in the first stages of LOAD, and this phenomenon might be related with systemic inflammation. The finding of lower 24S-OH-Chol concentrations in VD might be related with a more advanced stage of VD compared with LOAD in our sample, and/or to different pathogenetic mechanisms and evolution of these two forms of dementia.</p

A divergent role for estrogen receptor-beta in node-positive and node-negative breast cancer classified according to molecular subtypes: an observational prospective study

Introduction: Estrogen receptor-alpha (ER-alpha) and progesterone receptor (PgR) are consolidated predictors of response to hormonal therapy (HT). In contrast, little information regarding the role of estrogen receptor-beta (ER-beta) in various breast cancer risk groups treated with different therapeutic regimens is available. In particular, there are no data concerning ER-beta distribution within the novel molecular breast cancer subtypes luminal A (LA) and luminal B (LB), HER2 (HS), and triple-negative (TN). Methods: We conducted an observational prospective study using immunohistochemistry to evaluate ER-beta expression in 936 breast carcinomas. Associations with conventional biopathological factors and with molecular subtypes were analyzed by multiple correspondence analysis (MCA), while univariate and multivariate Cox regression analysis and classification and regression tree analysis were applied to determine the impact of ER-beta on disease-free survival in the 728 patients with complete follow-up data. Results: ER-beta evenly distributes (55.5%) across the four molecular breast cancer subtypes, confirming the lack of correlation between ER-beta and classical prognosticators. However, the relationships among the biopathological factors, analyzed by MCA, showed that ER-beta positivity is located in the quadrant containing more aggressive phenotypes such as HER2 and TN or ER-alpha/PgR/Bcl2- tumors. Kaplan-Meier curves and Cox regression analysis identified ER-beta as a significant discriminating factor for disease-free survival both in the node-negative LA (P = 0.02) subgroup, where it is predictive of response to HT, and in the node-positive LB (P = 0.04) group, where, in association with PgR negativity, it conveys a higher risk of relapse. Conclusion: Our data indicated that, in contrast to node-negative patients, in node-positive breast cancer patients, ER-beta positivity appears to be a biomarker related to a more aggressive clinical course. In this context, further investigations are necessary to better assess the role of the different ER-beta isoforms

Fenretinide: ap53-indipendent way to kill cancer cells.

The synthetic retinoid fenretinide [N-(4 hydroxyphenyl)retinamide] induces apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs, thus providing opportunities for novel approaches to cancer therapy. The upstream signaling events induced by fenretinide include an increase in intracellular levels of ceramide, which is subsequently metabolized to GD3. This ganglioside triggers the activation of 12-Lox (12-lipoxygenase) leading to oxidative stress and apoptosis via the induction of the transcription factor Gadd153 and the Bcl-2-family member protein Bak. Increased evidence suggests that the apoptotic pathway activated by fenretinide is p53-independent and this may represent a novel way to treat tumors resistant to DNA-damaging chemotherapeutic agents. Therefore, fenretinide offers increased clinical benefit as a novel agent for cancer therapy, able to complement the action of existing chemotherapeutic treatment regimes. Furthermore, synergy between fenretinide and chemotherapeutic drugs may facilitate the use of chemotherapeutic drugs at lower concentrations, with possible reduction in treatment-associated morbidity

Presence and incidence of DNA sequences of human polyomaviruses BKV and JCV in colon-rectal tumor tissues

Abstract. The human polyomaviruses JCV and BKV are widespread within population, as shown by serological studies. However, exposure to these viruses does not seem to have pathological consequences in immunocompetent individuals, while in immunocompromised or immunosuppressed patients, polyomaviruses can be activated, giving rise to serious pathologies. Viral DNA sequences were also found in cells from a number of human tumors of mesothelial origin, suggesting that activation of BKV and JCV, taking place in genetically predisposed and/or in immunodepressed individuals, might be involved in the mechanisms of tumor transformation. In this study, samples obtained from 18 patients with colon rectal carcinoma were probed for the presence of JCV and BKV by three different techniques: Southern blot, PCR and in situ hybridization. Our results demonstrate that viral DNA sequences were present in 16 out of the 18 cases considered (88.9%). In the large majority of cases, viruses were detected both in the tumor mass and in the surrounding healthy tissues. Lymphocytes in the investigated areas were also found to be infected by polyomaviruses. These data indicate, for the first time, a possible involvement of polyomaviruses in the pathogenesis of tumors of endothelial origin, like the human colon rectal carcinoma

Non-Hodgkin lymphomas concurrent with HHV8-associated Kaposi's sarcoma in the same lymph node in AIDS and non-AIDS patients

Background: The association between lymphomas and Kaposi's sarcoma has been described since 1920. The simultaneous presence of the 2 pathologic entities within the same lymph node is a rare and interesting occurrence. In the few cases described, the presence of human herpesvirus 8 (HHV8) and Epstein-Barr virus (EBV) in the different neoplastic areas was investigated only by immunohistochemistry and in situ hybridization studies. Methods: Two cases of concurrent non-Hodgkin lymphoma and Kaposi's sarcoma in the same lymph node are described: a diffuse large B cell lymphoma in an AIDS patient and a T cell-rich large B cell lymphoma in a HIV-negative patient, complete with the clinical, immunohistological and molecular features, the latter ones defined after isolation of the different neoplastic areas by laser capture microdissection. Results: Polymerase chain reaction assays revealed HHV8 DNA sequences only in the microdissected Kaposi's sarcoma areas and EBV DNA sequences only in the lymphomatous areas in both cases, confirming the HHV8 infection only in the neoplastic sarcomatous cells and evidencing the EBV infection only in the lymphomatous cells. Conclusion: This study represents a further confirmation of the supposed different etiopathogenic mechanisms of the 2 neoplasias, suggesting a coincidental occurrence even when localized in the same lymph node, independently from HIV infection. Copyright © 2007 S. Karger AG